The Two Faces of p53 in Embryonic Stem Cells
When damage occurs such as UV radiation, p53 expression plays a dual role in embryonic cells. Its expression both removes the unhealthy cells from the stem-cell pool by promoting programmed cell death or differentiation. At the same time, p53 activates the Wnt pathway to inhibit the differentiation of surrounding, healthy embryonic stem cells to maintain a population for the development of the organism.
Mutations in the genome of a cell can have dire effects. This type of damage can be even more devastating if it occurs in stem cells, since any changes will be passed on to all subsequent generations. Consequently, there are many checkpoints to alert cellular machinery of changes in the DNA.
p53 monitors cells for damage from many types of environmental stress and is a type of protein called a transcription factor. Transcription factors bind to DNA at specific sites and facilitate the expression of genes. When damage occurs, p53 activates specific pathways to assess the damage and prevent its spread by inhibiting cell division or causing the cell to undergo programmed cell death.
Although extensive research on the functions of p53 has been done in adult cells, its roles in embryonic stem cells are poorly defined. Kyoung-Hwa Lee, Ph.D., a postdoctoral fellow working with Dr. Jing Huang in the CCR Laboratory of Cancer Biology and Genetics, has been studying the properties of embryonic stem cells in order to tap their potential for regenerative therapies. A recent report in The Proceedings of the National Academy of Sciences outlines the work of Dr. Lee and her colleagues that resulted in the identification of a mechanism used by p53 to control the fate of mouse embryonic stem cells.
To determine the genes affected by p53 in mouse embryonic stem cells, the scientists identified the p53 binding sites on cellular DNA using a genome-wide approach. A comparison was made between the binding of p53 in normal cells and in cells with DNA damage from exposure to a chemical agent. The experiment showed that p53 binds to many genes in both the healthy and damaged mouse cells. However, when DNA damage occurs, p53 is converted to its active state. These findings suggest that p53 positions itself on the DNA in healthy cells so that it is in place to respond quickly should damage occur.
Activation of p53 by DNA damage triggered several pathways implicated in the development of cancer, including the Wnt signaling pathway. The connection to p53 was puzzling at first since Wnt signaling has been shown to deter differentiation of embryonic stem cells and p53 promotes this outcome.
To unravel this apparent paradox, the scientists measured the ability of p53 to induce Wnt production. Experiments in cultured mouse embryonic stem cells showed that after DNA damage with UV radiation, the cells secreted specific Wnt proteins into the culture media, which inhibits differentiation of surrounding cells. If the cells were modified to remove p53, Wnt production was diminished.
The ability of p53 to both promote and inhibit the differentiation of embryonic stem cells originates from its role as a monitor of the cellular environment. When damage occurs, p53 removes the unhealthy cells from the stem-cell pool by promoting programmed cell death or differentiation. At the same time, p53 activates the Wnt pathway to inhibit the differentiation of surrounding, healthy embryonic stem cells to maintain a population for the development of the organism.Summary Posted: Tue, 12/01/2009
Proc Natl Acad Sci USA. 2009 Dec 14 [Epub ahead of print] PubMed Link